Lgr5+ telocytes are a signaling source at the intestinal villus tip

Keren Bahar Halpern; Hassan Massalha; Rachel K. Zwick; Andreas E. Moor; David Castillo-Azofeifa; Milena Rozenberg; Lydia Farack; Adi Egozi; Dan R. Miller; Inna Averbukh; Yotam Harnik; Noa Weinberg-Corem; Frederic J. de Sauvage; Ido Amit; Ophir D. Klein; Michal Shoshkes-Carmel; Shalev Itzkovitz

doi:10.1038/s41467-020-15714-x

Lgr5+ telocytes are a signaling source at the intestinal villus tip

Keren Bahar Halpern, Hassan Massalha, Rachel K. Zwick, Andreas E. Moor, David Castillo-Azofeifa, Milena Rozenberg, Lydia Farack, Adi Egozi, Dan R. Miller, Inna Averbukh, Yotam Harnik, Noa Weinberg-Corem, Frederic J. de Sauvage, Ido Amit, Ophir D. Klein, Michal Shoshkes-Carmel, Shalev Itzkovitz^*

^*Corresponding author for this work

Department of Developmental Biology and Cancer Research

Research output: Contribution to journal › Article › peer-review

96 Scopus citations

Abstract

The intestinal epithelium is a structured organ composed of crypts harboring Lgr5+ stem cells, and villi harboring differentiated cells. Spatial transcriptomics have demonstrated profound zonation of epithelial gene expression along the villus axis, but the mechanisms shaping this spatial variability are unknown. Here, we combine laser capture micro-dissection and single cell RNA sequencing to uncover spatially zonated populations of mesenchymal cells along the crypt-villus axis. These include villus tip telocytes (VTTs) that express Lgr5, a gene previously considered a specific crypt epithelial stem cell marker. VTTs are elongated cells that line the villus tip epithelium and signal through Bmp morphogens and the non-canonical Wnt5a ligand. Their ablation is associated with perturbed zonation of enterocyte genes induced at the villus tip. Our study provides a spatially-resolved cell atlas of the small intestinal stroma and exposes Lgr5+ villus tip telocytes as regulators of the epithelial spatial expression programs along the villus axis.

Original language	English
Article number	1936
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-15714-x
State	Published - 1 Dec 2020

Bibliographical note

Funding Information:
S.I. is supported by the Henry Chanoch Krenter Institute for Biomedical Imaging and Genomics, The Leir Charitable Foundations, Richard Jakubskind Laboratory of Systems Biology, Cymerman-Jakubskind Prize, The Lord Sieff of Brimpton Memorial Fund, the I-CORE program of the Planning and Budgeting Committee and the Israel Science Foundation (grants 1902/ 12 and 1796/12), the Israel Science Foundation grant No. 1486/16, the Broad Institute-Israel Science Foundation grant No. 2615/18, the Chan Zuckerberg Initiative grant No. CZF2019-002434, the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013)/ERC grant agreement number 335122, the Bert L. and N. Kuggie Vallee Foundation and the Howard Hughes Medical Institute (HHMI) international research scholar award. O.D.K. is supported by NIH R35-DE026602 and U01-DK103147.

Publisher Copyright:
© 2020, The Author(s).

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Bahar Halpern, K., Massalha, H., Zwick, R. K., Moor, A. E., Castillo-Azofeifa, D., Rozenberg, M., Farack, L., Egozi, A., Miller, D. R., Averbukh, I., Harnik, Y., Weinberg-Corem, N., de Sauvage, F. J., Amit, I., Klein, O. D., Shoshkes-Carmel, M., & Itzkovitz, S. (2020). Lgr5+ telocytes are a signaling source at the intestinal villus tip. Nature Communications, 11(1), Article 1936. https://doi.org/10.1038/s41467-020-15714-x

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abstract = "The intestinal epithelium is a structured organ composed of crypts harboring Lgr5+ stem cells, and villi harboring differentiated cells. Spatial transcriptomics have demonstrated profound zonation of epithelial gene expression along the villus axis, but the mechanisms shaping this spatial variability are unknown. Here, we combine laser capture micro-dissection and single cell RNA sequencing to uncover spatially zonated populations of mesenchymal cells along the crypt-villus axis. These include villus tip telocytes (VTTs) that express Lgr5, a gene previously considered a specific crypt epithelial stem cell marker. VTTs are elongated cells that line the villus tip epithelium and signal through Bmp morphogens and the non-canonical Wnt5a ligand. Their ablation is associated with perturbed zonation of enterocyte genes induced at the villus tip. Our study provides a spatially-resolved cell atlas of the small intestinal stroma and exposes Lgr5+ villus tip telocytes as regulators of the epithelial spatial expression programs along the villus axis.",

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Bahar Halpern, K, Massalha, H, Zwick, RK, Moor, AE, Castillo-Azofeifa, D, Rozenberg, M, Farack, L, Egozi, A, Miller, DR, Averbukh, I, Harnik, Y, Weinberg-Corem, N, de Sauvage, FJ, Amit, I, Klein, OD, Shoshkes-Carmel, M & Itzkovitz, S 2020, 'Lgr5+ telocytes are a signaling source at the intestinal villus tip', Nature Communications, vol. 11, no. 1, 1936. https://doi.org/10.1038/s41467-020-15714-x

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AU - Egozi, Adi

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AU - Averbukh, Inna

AU - Harnik, Yotam

AU - Weinberg-Corem, Noa

AU - de Sauvage, Frederic J.

AU - Amit, Ido

AU - Klein, Ophir D.

AU - Shoshkes-Carmel, Michal

AU - Itzkovitz, Shalev

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Lgr5+ telocytes are a signaling source at the intestinal villus tip

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